Cell therapies have emerged as a promising therapeutic modality with the potential to treat and even cure a diverse array of diseases. Cell therapies offer unique clinical and therapeutic advantages over conventional small molecules and the growing number of biologics. Particularly, living cells can simultaneously and dynamically perform complex biological functions in ways that conventional drugs cannot; cell therapies have expanded the spectrum of available therapeutic options to include key cellular functions and processes. As such, cell therapies are currently one of the most investigated therapeutic modalities in both preclinical and clinical settings, with many products having been approved and many more under active clinical investigation. Here, we highlight the diversity and key advantages of cell therapies and discuss their current clinical advances. In particular, we review 28 globally approved cell therapy products and their clinical use. We also analyze >1700 current active clinical trials of cell therapies, with an emphasis on discussing their therapeutic applications. Finally, we critically discuss the major biological, manufacturing, and regulatory challenges associated with the clinical translation of cell therapies.

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A new modality in microbe-mediated drug delivery has recently emerged wherein genetically engineered microbes are used to locally deliver recombinant therapeutic proteins to the gastrointestinal tract. These engineered microbes are often referred to as live biotherapeutic products (LBPs). Despite advanced genetic engineering and recombinant protein expression approaches, little is known on how to control the spatiotemporal dynamics of LBPs and their secreted therapeutics within the gastrointestinal tract. To date, the fundamental pharmacokinetic analyses for microbe-mediated drug delivery systems have not been described. Here, we explore the pharmacokinetics of an engineered, model protein-secreting Saccharomyces cerevisiae, which serves as an ideal organism for the oral delivery of complex, post-translationally modified proteins. We establish three methods to modulate the pharmacokinetics of an engineered, recombinant protein-secreting fungi system: (i) altering oral dose of engineered fungi, (ii) coadministering antibiotics, and (iii) altering recombinant protein secretion titer. Our findings establish the fundamental pharmacokinetics which will be essential in controlling downstream therapeutic response for this new delivery modality.

A new modality in antibody engineering has emerged in which the antigen affinity is designed to be pH dependent (PHD). In particular, combining high affinity binding at neutral pH with low affinity binding at acidic pH leads to a novel antibody that can more effectively neutralize the target antigen while avoiding antibody-mediated antigen accumulation. Here, we studied how the in vivo pharmacokinetics of the superantigen, Staphylococcal enterotoxin B (SEB), is affected by an engineered antibody with pH-dependent binding. PHD anti-SEB antibodies were engineered by introducing mutations into a high affinity anti-SEB antibody, 3E2, by rational design and directed evolution. Three antibody mutants engineered in the study have an affinity at pH 6.0 that is up to 68-fold weaker than the control antibody. The pH dependency of each mutant, measured as the pHdependent affinity ratio (PARratio of affinity at pH 7.4 and pH 6.0), ranged from 6.7-11.5 compared to 1.5 for the control antibody. The antibodies were characterized in mice by measuring their effects on the pharmacodynamics and pharmacokinetics (PK) of SEB after co-administration. All antibodies were effective in neutralizing the toxin and reducing the toxin-induced cytokine production. However, engineered PHD antibodies led to significantly faster elimination of the toxin from the circulation than wild type 3E2. The area under the curve computed from the SEB PK profile correlated well with the PAR value of antibody, indicating the importance of fine tuning the pH dependency of binding. These results suggest that a PHD recycling antibody may be useful to treat intoxication from a bacterial toxin by accelerating its clearance. ARTICLE HISTORY